siRNA-L2 achieves superior delivery to PDX and orthotopic tumors. Biodistribution was evaluated using a nontoxic dose of 1, 10 mg/kg of siRNA-L2 and the MTD of 1 mg/kg jetPEI NPs. (A–F) Orthotopic model: (A) Absolute organ radiance for siRNA-L2 (10 mg/kg), jet PEI NPs (1 mg/kg). (B) Fraction organ radiance for siRNA-L2, jetPEI NPs. (C) Absolute tumor radiance; exponential decay fits plotted. (D) Fraction tumor radiance; **P < 0.01. (E) Tumor:liver ratio reveals a lower proportion in the liver for siRNA-L2 in comparison with jetPEI NPs. n = 4, SE plotted. (F) Representative images depicting accumulation in liver, tumors. (G and H) PDX model: (G) Biodistribution and (H) plotted tumor radiance (n = 2) of dose-matched jetPEI NPs and siRNA-L2 at 24 h. Radiance units are photons per second per square centimeter per steradian.